The Mutation Rate and Cancer

Genetics ◽  
1998 ◽  
Vol 148 (4) ◽  
pp. 1483-1490 ◽  
Author(s):  
Aimee L Jackson ◽  
Lawrence A Loeb
Keyword(s):  
Mutation Rate ◽  
Somatic Mutations ◽  
Environmental Changes ◽  
Germ Line ◽  
Rna Viruses ◽  
Spontaneous Mutation ◽  
Mutation Rates ◽  
Major Question ◽  
Spontaneous Mutation Rate ◽  
The Stability

Abstract The stability of the human genome requires that mutations in the germ line be exceptionally rare events. While most mutations are neutral or have deleterious effects, a limited number of mutations are required for adaptation to environmental changes. Drake has provided evidence that DNA-based microbes have evolved a mechanism to yield a common spontaneous mutation rate of ~0.003 mutations per genome per replication (Drake 1991). In contrast, mutation rates of RNA viruses are much larger (Holland et al. 1982) and can approach the maximum tolerable deleterious mutation rate of one per genome (Eigen and Schuster 1977; Eigen 1993). Drake calculates that lytic RNA viruses display spontaneous mutation rates of approximately one per genome while most have mutation rates that are approximately 0.1 per genome (Drake 1993). This constancy of germline mutation rates among microbial species need not necessarily mean constancy of the somatic mutation rates. Furthermore, there need not be a constant rate for somatic mutations during development. In this review, we consider mutations in cancer, a pathology in which there appears to be an increase in the rate of somatic mutations throughout the genome. Moreover, within the eukaryotic genome, as in microbes, there are “hot-spots” that exhibit unusually high mutation frequencies. It seems conceivable to us that many tumors contain thousands of changes in DNA sequence. The major question is: how do these mutations arise, and how many are rate-limiting for tumor progression?

scholarly journals The Rate and Character of Spontaneous Mutation in an RNA Virus

Genetics ◽  
2002 ◽  
Vol 162 (4) ◽  
pp. 1505-1511 ◽  
Author(s):  
José M Malpica ◽  
Aurora Fraile ◽  
Ignacio Moreno ◽  
Clara I Obies ◽  
John W Drake ◽  
...  
Keyword(s):  
Mutation Rate ◽  
Movement Protein ◽  
Rna Viruses ◽  
Rna Virus ◽  
Spontaneous Mutation ◽  
Mutation Rates ◽  
Lower Side ◽  
Mutation Process ◽  
Spontaneous Mutation Rate ◽  
Mutant Frequency

Abstract Estimates of spontaneous mutation rates for RNA viruses are few and uncertain, most notably due to their dependence on tiny mutation reporter sequences that may not well represent the whole genome. We report here an estimate of the spontaneous mutation rate of tobacco mosaic virus using an 804-base cognate mutational target, the viral MP gene that encodes the movement protein (MP). Selection against newly arising mutants was countered by providing MP function from a transgene. The estimated genomic mutation rate was on the lower side of the range previously estimated for lytic animal riboviruses. We also present the first unbiased riboviral mutational spectrum. The proportion of base substitutions is the same as that in a retrovirus but is lower than that in most DNA-based organisms. Although the MP mutant frequency was 0.02-0.05, 35% of the sequenced mutants contained two or more mutations. Therefore, the mutation process in populations of TMV and perhaps of riboviruses generally differs profoundly from that in populations of DNA-based microbes and may be strongly influenced by a subpopulation of mutator polymerases.

scholarly journals First Estimation of the Spontaneous Mutation Rate in Diatoms

2019 ◽  
Vol 11 (7) ◽  
pp. 1829-1837 ◽  
Author(s):  
Marc Krasovec ◽  
Sophie Sanchez-Brosseau ◽  
Gwenael Piganeau
Keyword(s):  
Mutation Rate ◽  
Spontaneous Mutation ◽  
Mutation Accumulation ◽  
Mutation Rates ◽  
Model Organisms ◽  
Base Substitution ◽  
Unicellular Eukaryote ◽  
Fundamental Parameter ◽  
Secondary Endosymbiosis ◽  
Spontaneous Mutation Rate

Abstract Mutations are the origin of genetic diversity, and the mutation rate is a fundamental parameter to understand all aspects of molecular evolution. The combination of mutation–accumulation experiments and high-throughput sequencing enabled the estimation of mutation rates in most model organisms, but several major eukaryotic lineages remain unexplored. Here, we report the first estimation of the spontaneous mutation rate in a model unicellular eukaryote from the Stramenopile kingdom, the diatom Phaeodactylum tricornutum (strain RCC2967). We sequenced 36 mutation accumulation lines for an average of 181 generations per line and identified 156 de novo mutations. The base substitution mutation rate per site per generation is μbs = 4.77 × 10−10 and the insertion–deletion mutation rate is μid = 1.58 × 10−11. The mutation rate varies as a function of the nucleotide context and is biased toward an excess of mutations from GC to AT, consistent with previous observations in other species. Interestingly, the mutation rates between the genomes of organelles and the nucleus differ, with a significantly higher mutation rate in the mitochondria. This confirms previous claims based on indirect estimations of the mutation rate in mitochondria of photosynthetic eukaryotes that acquired their plastid through a secondary endosymbiosis. This novel estimate enables us to infer the effective population size of P. tricornutum to be Ne∼8.72 × 106.

MUTATION RATES FOR ENZYME AND MORPHOLOGICAL LOCI IN BARLEY (HORDEUM VULGARE L.)

Genetics ◽  
1984 ◽  
Vol 106 (4) ◽  
pp. 729-734
Author(s):  
A L Kahler ◽  
R W Allard ◽  
R D Miller
Keyword(s):  
Mutation Rate ◽  
Spontaneous Mutation ◽  
Mutation Rates ◽  
Isogenic Line ◽  
Probability Level ◽  
Short Term ◽  
Hordeum Vulgare L ◽  
Spontaneous Mutation Rate ◽  
Enzyme Loci ◽  
Morphological Variants

ABSTRACT Spontaneous mutation rates were estimated by assaying 84,126 seedlings of a highly homozygous barley line (isogenic line 2025) for five enzyme loci. No mutants were observed in 841,260 allele replications. This result excludes, at probability level 0.95, a spontaneous mutation rate larger than 3.56 x 10-6/locus/gamete/generation for these enzyme loci. Isogenic line 2025 also was scored for mutants at four loci governing morphological variants. No mutants were observed in 3,386,850 allele replications which indicates that the upper bound for the mutation rate for these loci is 8.85 x 10-7. It was concluded that, even though spontaneous mutation has been important in creating variability in the barley species at the loci scored, the rate is too low to have much affect on the short-term dynamics of barley populations.

scholarly journals MUTATOR ACTIVITY OF PETITE STRAINS OF SACCHAROMYCES CEREVISIAE

Genetics ◽  
1976 ◽  
Vol 83 (4) ◽  
pp. 645-653
Author(s):  
Fred Flury ◽  
R C von Borstel ◽  
D H Williamson
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Mitochondrial Dna ◽  
Mutation Rate ◽  
Frameshift Mutation ◽  
Spontaneous Mutation ◽  
Nuclear Genes ◽  
Mutation Rates ◽  
Spontaneous Mutation Rate ◽  
Mutator Activity ◽  
Missense Allele

ABSTRACT Petite strains in Saccharomyces exhibit enhanced spontaneous mutation rates of nuclear genes regardless of whether they are cytoplasmically or nuclearly inherited, or whether or not the cytoplasmic petite strains have mitochondrial DNA. In petite strains, the mutation rate for the nonsense allele lys1-1 is enhanced by a factor of 3-6 and for the missense allele his1-7 by a factor of 2 as compared with their grande counterparts. The reversion of a third allele, the putative frameshift mutation, hom3-10, is not enhanced in a petite background. The results indicate that the spontaneous mutation rate of an organism can be altered by indirect intracellular influences.

Increased spontaneous DNA damage in Cu/Zn superoxide dismutase (SOD1) deficient Drosophila

Genome ◽  
2004 ◽  
Vol 47 (6) ◽  
pp. 1029-1035 ◽  
Author(s):  
R C Woodruff ◽  
J P Phillips ◽  
A J Hilliker
Keyword(s):  
Superoxide Dismutase ◽  
Somatic Mutations ◽  
Germ Line ◽  
Spontaneous Mutation ◽  
Somatic Cells ◽  
Reactive Oxygen ◽  
Spontaneous Mutation Rate ◽  
Genomic Damage ◽  
Recessive Phenotype ◽  
By Products

The superoxide dismutases (SODs) protect oxygen-using cells against reactive oxygen species, the potentially toxic by-products of respiration, oxidative metabolism, and radiation. We have previously shown that genetic disruption of CuZn SOD (SOD1) in Drosophila imparts a recessive phenotype of reduced lifespan, infertility, and hypersensitivity to oxidative stress. We now show that the absence of SOD1 increases spontaneous genomic damage. The increase in spontaneous mutation rate occurs in SOD1-null mutants in somatic cells as well as in the germ line. Further, we show that specific DNA repair-defective mutations, which are easily tolerated in SOD1+ flies, lead to high mortality when introduced into the SOD1-null homozygous mutant background.Key words: Drosophila melanogaster, superoxide dismutase, mutations, germ and somatic cells, lethal and somatic mutations, reactive oxygen.

scholarly journals Deoxyribonucleic Acid Damage and Spontaneous Mutagenesis in the Thyroid Gland of Rats and Mice

Endocrinology ◽  
2006 ◽  
Vol 147 (7) ◽  
pp. 3391-3397 ◽  
Author(s):  
J. Maier ◽  
H. van Steeg ◽  
C. van Oostrom ◽  
S. Karger ◽  
R. Paschke ◽  
...  
Keyword(s):  
Comet Assay ◽  
Mutation Rate ◽  
High Frequency ◽  
Somatic Mutations ◽  
Spontaneous Mutation ◽  
Point Mutations ◽  
Fold Increase ◽  
Thyroid Tumors ◽  
Apparent Contradiction ◽  
Spontaneous Mutation Rate

Thyroid tumors are a frequent finding not only in iodine-deficient regions. They are predominantly characterized by somatic genetic changes (e.g. point mutations or rearrangements). Because slow thyroid proliferation is a apparent contradiction to a high frequency of tumor initiation, we characterized mutational events in thyroid. First we studied the frequency of certain base exchanges in somatic TSH receptor (TSHR) mutations and determined the spontaneous mutation rate in thyroid and liver. Then we applied different protocols of the comet assay to quantify genomic DNA damage and conducted immunohistochemistry for 8-oxoguanine as a molecular marker for oxidative stress. Among 184 somatic mutations of the human TSHR found in thyroid tumors, C→T transitions had a unexpectedly high frequency (>32%). The mutation rate in thyroid is 8–10 times higher than in other organs. The comet assay detected increased levels of oxidized pyrimidine (2- to 3-fold) and purine (2- to 4-fold) in thyroid, compared with liver and lung, and a 1.6-fold increase of oxidized purine, compared with spleen. Immunohistochemistry revealed high levels of 8-oxoguanine in thyroid epithelial cells. We have shown a strikingly high mutation rate in the thyroid. Furthermore, results of the comet assay as well as immunohistochemistry suggest that oxidative DNA modifications are a likely cause of the higher mutation rate. It is possible that free radicals resulting from reactive oxygen species in the thyroid generate mutations more frequently. This is also supported by the spectrum of somatic mutations in the TSHR because more frequent base changes could stem from oxidized base adducts that we detected in the comet assay and with immunohistochemistry.

scholarly journals On the evolutionary adjustment of spontaneous mutation rates

1967 ◽  
Vol 9 (1) ◽  
pp. 23-34 ◽  
Author(s):  
Motoo Kimura
Keyword(s):  
Population Genetics ◽  
Natural Selection ◽  
Mutation Rate ◽  
Spontaneous Mutation ◽  
Genetic Material ◽  
Genetic Load ◽  
Mutation Rates ◽  
Spontaneous Mutation Rate ◽  
Physiological Limit ◽  
Present Mode

Evolutionary factors which tend to decrease the mutation rate through natural selection and those which tend to increase the mutation rate are discussed from the standpoint of population genetics. The author's theory of optimum mutation rate based on the principle of minimum genetic load is re-examined, assuming that mutation rate is adjusted in the course of evolution in such a way that the sum of mutational and substitutional load is minimized. Another hypothesis is also examined that only selection toward lowering the mutation rate is effective and the present mutation rate in each organism represents the physical or physiological limit that may be attained by natural selection.The possibility cannot be excluded that the spontaneous mutation rate is near the minimum that may be attained under the present mode of organization of the genetic material, and at the same time is not very far from the optimum in the sense of minimizing the genetic load.

scholarly journals Evolution of Mutation Rate in Astronomically Large Phytoplankton Populations

2020 ◽  
Vol 12 (7) ◽  
pp. 1051-1059
Author(s):  
Marc Krasovec ◽  
Rosalind E M Rickaby ◽  
Dmitry A Filatov
Keyword(s):  
Genetic Diversity ◽  
Population Size ◽  
Mutation Rate ◽  
Spontaneous Mutation ◽  
Large Population ◽  
Marine Phytoplankton ◽  
Mutation Rates ◽  
Effective Population ◽  
Spontaneous Mutation Rate ◽  
Large Populations

Abstract Genetic diversity is expected to be proportional to population size, yet, there is a well-known, but unexplained lack of genetic diversity in large populations—the “Lewontin’s paradox.” Larger populations are expected to evolve lower mutation rates, which may help to explain this paradox. Here, we test this conjecture by measuring the spontaneous mutation rate in a ubiquitous unicellular marine phytoplankton species Emiliania huxleyi (Haptophyta) that has modest genetic diversity despite an astronomically large population size. Genome sequencing of E. huxleyi mutation accumulation lines revealed 455 mutations, with an unusual GC-biased mutation spectrum. This yielded an estimate of the per site mutation rate µ = 5.55×10−10 (CI 95%: 5.05×10−10 – 6.09×10−10), which corresponds to an effective population size Ne ∼ 2.7×106. Such a modest Ne is surprising for a ubiquitous and abundant species that accounts for up to 10% of global primary productivity in the oceans. Our results indicate that even exceptionally large populations do not evolve mutation rates lower than ∼10−10 per nucleotide per cell division. Consequently, the extreme disparity between modest genetic diversity and astronomically large population size in the plankton species cannot be explained by an unusually low mutation rate.

scholarly journals Rates of spontaneous mutation in bacteriophage T4 are independent of host fidelity determinants.

Genetics ◽  
1994 ◽  
Vol 138 (3) ◽  
pp. 553-564 ◽  
Author(s):  
M E Santos ◽  
J W Drake
Keyword(s):  
Dna Polymerase ◽  
Mutation Rate ◽  
Excision Repair ◽  
Bacteriophage T4 ◽  
Spontaneous Mutation ◽  
Resolving Power ◽  
Mutation Rates ◽  
Spontaneous Mutation Rate ◽  
Dntp Pool ◽  
Host Fidelity

Abstract Bacteriophage T4 encodes most of the genes whose products are required for its DNA metabolism, and host (Escherichia coli) genes can only infrequently complement mutationally inactivated T4 genes. We screened the following host mutator mutations for effects on spontaneous mutation rates in T4: mutT (destruction of aberrant dGTPs), polA, polB and polC (DNA polymerases), dnaQ (exonucleolytic proofreading), mutH, mutS, mutL and uvrD (methyl-directed DNA mismatch repair), mutM and mutY (excision repair of oxygen-damaged DNA), mutA (function unknown), and topB and osmZ (affecting DNA topology). None increased T4 spontaneous mutation rates within a resolving power of about twofold (nor did optA, which is not a mutator but overexpresses a host dGTPase). Previous screens in T4 have revealed strong mutator mutations only in the gene encoding the viral DNA polymerase and proofreading 3'-exonuclease, plus weak mutators in several polymerase accessory proteins or determinants of dNTP pool sizes. T4 maintains a spontaneous mutation rate per base pair about 30-fold greater than that of its host. Thus, the joint high fidelity of insertion by T4 DNA polymerase and proofreading by its associated 3'-exonuclease appear to determine the T4 spontaneous mutation rate, whereas the host requires numerous additional systems to achieve high replication fidelity.

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